Spanish patent ES2084801T (equivalent to European patent EP 443983) describes acyl compounds, one of them is Valsartan of formula (I):

Said Spanish patent describes the preparation of Valsartan by converting a phenyl substituent (Z1) into tetrazole, where Z1 is a group convertible into tetrazole. The examples of said patent describe the specific case in which Z1 is a cyano group or a protected tetrazole ring. This is followed by final deprotection of the carboxylic acid group, where R is preferably methyl or benzyl and, if this is the case, of the tetrazole ring protecting group, preferably a trityl group.

This patent leaves aspects to be improved, such as the use of azide in the last synthesis steps, with the attendant risk of explosions if sodium azide is used, or environmental problems if tributyl tin azide is used.
Another negative aspect lies in the use of bulky protective groups both for the tetrazole ring (trityl group) and the carboxylic acid of the valine moiety (benzyl group), which very considerably increase the molecular weight of the last synthesis intermediate. This molecular weight is drastically reduced in the final hydrolysis to give Valsartan, thus resulting in a process of low atomic efficiency. This further creates a considerable amount of residues and increases the number of synthesis steps in the process.
Patents DE4313747, DE4407488, U.S. Pat. No. 5,596,006, EP594022 and WO9609301 describe the synthesis of sartans by formation of the biphenyl system by reacting an aryl halide with 2-(1H-tetrazol-5-yl)phenylboronic acid in the presence of a palladium catalyst.
European patent application EP1533305 describes a method for obtaining Valsartan by means of reductive amination reaction of a biphenyl aldehyde with protected L-valine with a benzyl group which has to be eliminated. The tetrazole group is formed in the penultimate step of the synthesis.
International patent application WO2004/026847 describes a similar process in which reductive amination of a biphenyl aldehyde takes place, in which the tetrazole group is previously formed and protected, with protected L-Valine in the carboxylic acid function.
There therefore still remains a need for a process for obtaining Valsartan that is safe, ecological and with high yields and few synthesis steps and from simple and commercially available starting products. Additionally, it must be possible to apply the process on an industrial scale and to avoid racemisation and the consequent separation of enantiomers.
Patent application ES200400949, incorporated herein in its entirety as reference, describes a process for the synthesis of Valsartan that includes reaction of the intermediate (II) with a boronic acid of formula (III) in order to give Valsartan (I):

Preparation of the Intermediate (II), in accordance with patent application ES200400949, comprises: a) alkylation of the L-Valine (IV) with a halide of formula (V) to give a compound of formula (VI) followed by b) acylation with valeryl chloride.

In the alkylation step the carboxylic acid must be protected in the form of silyl ester to prevent the formation of the benzyl ester. Furthermore, the dialkylation compound in the nitrogen of the L-Valine is inevitably formed in variable proportions and is difficult to eliminate.
In the acylation step of intermediate (VI), moreover, the reaction conditions are critical, and a restricted range of reaction parameters has to be used in order to prevent partial racemisation of compound (II) that would involve additional purifications.
This process presents disadvantages that hinder its application on an industrial scale and that are susceptible of improvement in order to reduce costs, generate less waste and improve the yield of the synthesis, as well as allow the utilisation of more easily handled reagents.